Glucocorticoids are by far the most commonly used immunosuppressive drugs. They affect nearly every tissue in the body to alter metabolism and suppress inflammation and immune responses in a dose-dependent fashion. Genomic transcription patterns and subsequent protein expression are altered, resulting in impaired cell mediated immunity, and to a lesser extent, impaired phagocytic and humoral immunity.5 A multitude of GCs are available that vary in potency and route of administration (Table 11.1). Based on data largely derived in other species, these drugs are described as short-, intermediate- or long-acting based on duration of suppression of the hypothalamic–pituitary–­adrenal axis (HPAA). Duration of action depends upon both the base compound and modifications, such as esterification, which alter GC absorption. For instance, although methylprednisolone is an intermediate-­acting compound, it is a very long-acting compound as the repositol formulation methylprednisolone acetate. When used to achieve chronic immunosuppression, intermediate-acting preparations (e.g., prednisolone) offer a practical dose regimen that can be tailored to produce efficacy while minimizing HPAA suppression and adverse effects. The most commonly prescribed GCs are prednisone or its active metabolite prednisolone. In cats, prednisolone is strongly preferred over prednisone due to a superior pharmacokinetic profile in the species, which reduces the variability in patient metabolism of a given dosage.⁶ The mechanism behind the disparity is not entirely clear but decreased gastrointestinal (GI) absorption of prednisone or diminished hepatic conversion of prednisone to prednisolone are suspected.

Surprisingly, there is no scientific evidence of exactly what constitutes an immunosuppressive dosage of prednisolone (or any other GC) in cats. Compared to dogs, cats are relatively resistant to many of the effects of GCs, perhaps due to lesser numbers of intracytoplasmic GC receptors.⁷ Typically, 2 to 4 mg/kg/day prednisolone is an initial immunosuppressive dosage while 0.5 to 2 mg/kg/day is the anti-inflammatory dosage range; prednisolone is typically given by mouth but comes in other formulations. Higher dosages were recommended in years past, perhaps based on clinical experience, using less biologically available prednisone instead of prednisolone. Biologically equivalent dosages of other GCs can be used in place of prednisolone (e.g., dexamethasone at 0.3 to 0.55 mg/kg/day as an immunosuppressive dosage). For immune-mediated or inflammatory disease especially, some veterinary dermatologists prefer to use methylprednisolone (0.8 to 2.2 mg/kg/day PO) or triamcinolone (0.06 to 0.26 mg/kg/day PO).⁸ For autoimmune disorders, the initial dosage is continued for several days past clinical remission and then gradually tapered. In general, for life-threatening disease, such as immune hemolytic anemia, the dose is reduced approximately 20% every 3 to 4 weeks while disease remains controlled; dermatologic conditions may warrant a more rapid taper. Clinical signs can provide a misleading impression of disease control; when possible, a measurable endpoint (e.g., hematocrit in cats with anemia) should be used.⁹ In some cases, GCs are continued at the lowest effective dosage for an indefinite (even lifelong) period. Although it is tempting to reduce dosages rapidly, early withdrawal may predispose to relapse. Long acting repositol formulations of GCs (e.g., methylprednisolone acetate injection) can be used when owners are unable to administer daily oral medications, but fine adjustments become impossible and adverse effects may be more likely.

Although cats are relatively resistant to the adverse effects of GCs, they can develop especially when used at high doses for extended periods. Polyuria, polydipsia, and polyphagia are less common adverse effects in cats than in dogs, but do occur, while a variety of other adverse effects of GCs have been documented or suggested (e.g., alopecia, pancreatitis).⁵ In addition to a stress leukogram, hyperglycemia, hyperalbuminemia, and hyperlipidemia were noted in healthy cats given prednisolone (4.4 mg/kg/day) or dexamethasone (0.55 mg/kg/day) for 56 days.¹⁰ The metabolic actions of GCs on glucose balance result in hyperglycemia in healthy cats, and some cats treated with GCs develop either temporary or permanent diabetes mellitus.^11,12 The diabetogenic effects of dexamethasone may be more pronounced than those of prednisolone.^10,11 The use of high dose, long-term systemic GCs should be avoided whenever possible in diabetic cats. Cardiac disease and especially congestive heart failure are also relative contraindications to GC use since GC-associated water retention may exacerbate congestive failure; water retention may be less with dexamethasone than prednisolone. As with any immunosuppressive therapy, an additional relative contraindication is infection.

Adverse effects of GCs can be minimized by limiting systemic exposure. In addition to using the lowest effective dosage of an intermediate-acting GC, this can be achieved via local application of GCs whenever possible. In some cases, GCs are formulated in such a way that systemic absorption is limited after local application and/or absorbed drug is rapidly inactivated through first pass hepatic metabolism. Inhaled budesonide has been used to treat feline asthma, and oral budesonide has at least anecdotal success in treating inflammatory bowel disease (IBD).^13,14 The desirability of this drug lies in limited systemic absorption and reduced clinical adverse effects. Similarly, application of the GCs fluticasone or flunisolide via nebulization or metered dose inhaler to the airway epithelium of cats with feline reactive ­airway disease (e.g., asthma) delivers the drug directly to the disease site.^15–18 Although the inciting cause of many diseases traditionally treated with immunosuppression may be unchecked inflammation, the disease may exert its consequences due to downstream effects, such as the bronchoconstriction that accompanies feline asthma. Some drugs combine a GC with another non-immunosuppressive drug to target both the inciting cause and the downstream effect, such as the combination of the bronchodilator salmeterol with inhaled ­fluticasone to decrease airway hyper-responsiveness and inflammation.¹⁸ These combinations make it more difficult to reduce the GC dose to the lowest effective dose. Although GCs are often efficacious, when adverse effects of GCs are pronounced or when GCs alone fail to control disease, alternative immunosuppressive drugs may allow a decrease in GC dose or may even permit discontinuation of GC therapy.

The most commonly used immunosuppressive drug in this class is cyclosporine. Cyclosporine inhibits T-cell activation and inhibits synthesis of cytokines such as interleukin-2 (IL-2) and gamma interferon while also reducing activation of antigen-presenting cells and phagocytes.19,20 Used extensively to prevent rejection of transplanted kidneys, cyclosporine has also been used to treat immune-mediated blood disorders in cats including immune hemolytic anemia, pure red cell and megakaryocytic aplasia, and immune thrombocytopenia.^21–25 Cyclosporine has also been used successfully to treat a variety of feline skin diseases, including atopic dermatitis, eosinophilic granuloma complex, proliferative eosinophilic keratitis, urticaria pigmentosa, pemphigus erythematosus and foliaceus, pruritus, atopic dermatitis, granulomatous folliculitis and furunculosis, as well as sebaceous adenitis.^26–31 Anecdotally, cyclosporine has been used to treat IBD in cats as well.³² Cyclosporine has been explored as an additional therapy for feline asthma with conflicting results. One experimental study suggested cyclosporine inhibited airway remodeling and inflammation and a case study was able to document resolution of eosinophilic lower airway inflammation in spontaneous disease.^33,34 However, another study found no change in initial asthmatic response or mast cell degranulation in experimentally sensitized animals.³⁵

Microemulsified formulations of cyclosporine (e.g., Atopica for Cats, Elanco) are preferred over the original nonaqueous suspension. An initial dosage of 5 mg/kg/day PO is reasonable, but individual variation in absorption, and multiple pharmacologic drug interactions (e.g., azole antifungals, omeprazole, metronidazole, phenobarbital, and many others), mean that dosage should be adjusted based upon measured drug trough concentration and patient response.^19,36–38 Lower dosages may be adequate for dermatologic disease, while higher dosages are required for organ transplantation. Difficulties in administering the product to cats orally due to palatability issues have led some veterinarians to prescribe compounded transdermal gels. Unfortunately, this cannot be recommended as therapeutic levels are rarely achieved.³⁹

As compared to other immunosuppressive therapies, cats tolerate cyclosporine well. Unlike cytostatic drugs, cyclosporine is not myelosuppressive. The most common adverse effect associated with cyclosporine is GI irritation and weight loss.⁴⁰ Hepatotoxicosis or nephrotoxicosis, while rare, are more serious.^19,27 Anaphylaxis has been reported in a single cat administered intravenous cyclosporine A, though the cat recovered and was able to tolerate oral cyclosporine A in oil.²⁴ Acute bullous keratopathy has been associated with chronic, systemic cyclosporine administration.⁴¹ There are multiple case reports of cats developing systemic toxoplasmosis during treatment with cyclosporine.^42–44 However, the risk may be greatest for cats initially infected after beginning cyclosporine rather than cats with positive titers when cyclosporine is begun.⁴⁵ Cats treated with cyclosporine should have retroviral status ascertained prior to starting the drug, and be monitored with a complete blood count (CBC) and serum chemistry profile at least three times per year. In a group of feline renal transplant patients treated with cyclosporine and prednisolone, malignant neoplasia occurred at more than six times the expected rate.^22,46

Tacrolimus is an immunophilin ligand immunosuppressive available in both oral and topical formulations which has a similar mechanism of action to ­cyclosporine. It is used in humans to prevent graft rejection, and has also been evaluated for prevention of renal allograft rejection in cats.⁴⁷ Clarithromycin, an inhibitor of P-glycoprotein and cytochrome 450, has been shown to increase bioavailability of tacrolimus in healthy cats, and may help decrease the treatment costs associated with the drug.⁴⁸ Tacrolimus 0.1% applied topically every 12–24 hours provided marked improvement in a small series of cats with proliferative and necrotizing otitis externa refractory to GC, antibiotic, and antifungal therapies.⁴⁹

Alkylating agents, which cause cross-linkage and strand breaks in DNA and RNA, are commonly used as chemotherapeutic drugs but they also act on lymphocyte populations, impairing both cell-mediated and humoral immunity. Because these agents require at least several weeks to become effective, they are started along with GCs and continued after the GCs are tapered or discontinued. The alkylating agent used most often as an immunosuppressant in cats is chlorambucil, but anecdotally cyclophosphamide has also been used. The clinical course of feline infectious peritonitis is believed to be due to a harmful immune response to the pathogen; while GCs may slow disease progression, cyclophosphamide was unable to do so.50 In our opinion, cyclophosphamide is best avoided for specific purposes of immunosuppression in cats.

Chlorambucil is used as an adjunctive or alternative to GCs in cats with immunologically mediated disease, although price increases have made this drug a less attractive option for immune suppression than in years past. Certainly, it has been used to treat cats with IBD, though it should be noted that IBD may be difficult to distinguish from GI lymphoma in cats so some positive response may be due to the action of chlorambucil in treatment of cancer rather than through immune suppression.^32,51,52 Chlorambucil combined with a GC was used effectively in a case of presumed paraneoplastic pemphigus vulgaris secondary to a thymoma.⁵³ Occasionally, alkylating agents have been used to treat hematologic disorders as well.^23,54 Chlorambucil is available in a 2-mg tablet form convenient for use in cats as a typical dose is 2 mg PO, with a dosing frequency of every 24 to 96 hours depending on response of the cat to treatment (dosing at 48 hour intervals is most common for IBD). Compounded liquid formulations should be avoided to minimize human exposure. Both chlorambucil and cyclophosphamide can induce myelosuppression, so a CBC must be monitored on a regular basis. Initially, a CBC should be checked 7 to 10 days after beginning therapy and should be monitored at least every 60 days; a serum chemistry profile should also be assessed periodically. Additional adverse effects include acquired Fanconi’s syndrome, GI upset, and myoclonus for chlorambucil and hemorrhagic cystitis for cyclophosphamide.^55–57

Cytostatic antimetabolite drugs mimic molecules which participate in cellular biochemical reactions but differ enough from the natural molecule to interfere with normal cell division and function. They include nucleic acid analogues as well as antifolate drugs. Most have a more profound effect on T lymphocytes (and therefore on cell-mediated immunity) than on B lymphocytes. Azathioprine is an antimetabolite commonly used to induce and maintain immunosuppression in dogs and humans. The drug is metabolized to 6-mercaptopurine (6-MP) which interferes with de novo purine synthesis. Unfortunately, a profound and potentially fatal myelosuppression occurs more commonly in cats treated with azathioprine than in dogs or humans, preventing its routine use in cats.^43,58 This difference in response of cats as compared to other species is likely the result of a relative deficiency in the enzyme which catalyzes the conversion of 6-MP to inactive metabolites.^59,60 Mycophenolate mofetil also inhibits de novo purine synthesis, and has been used to successfully treat immune-mediated hemolytic anemia in two cats without adverse effects.⁶¹ Pharmacologic data suggests that cats may require higher doses than other species to obtain adequate immunosuppression due their rapid metabolism of the drug, and optimal dose is undetermined.⁶²

Methotrexate is an antimetabolite used to treat rheumatoid arthritis in humans and is occasionally used for chemotherapy or as an immunosuppressive drug in cats. A dosage of 0.8 mg/kg IV every 2 to 3 weeks has been suggested, but there is little to document that this is safe or effective.⁶³ Methotrexate has been used in combination with another antimetabolite drug, leflunomide, in a small number of cats with spontaneous erosive rheumatoid arthritis.⁶⁴ Leflunomide has been used to treat dogs with a wide variety of immune-mediated diseases, but experience in cats is more limited. Leflunomide is converted to an active metabolite which inhibits an enzyme crucial for de novo pyrimidine synthesis. There has been some interest in the use of leflunomide for immunosuppression in feline renal transplantation since the drug possesses anti-herpesvirus activity.⁶⁵ Although not widely used clinically, potential adverse effects include GI irritation with oral administration and sedation if given intravenously.⁶⁶ It appears to have a lengthy half-life in cats, which raises concerns for possible cumulative effects.⁶⁶ The optimal dosage for leflunomide has yet to be determined; published dosages vary from an initial dosage of 10 mg per cat per day to more modest dosing schemes of 2 mg/kg PO every 48 hours or 10 mg per cat twice weekly.^64,66

Antibodies can be used for therapeutic immunomodulation. For instance, humanized murine monoclonal antibodies directed against the CD3 molecule on T lymphocyte receptors are effective in the prevention of organ rejection in people. CTLA4-Ig, an inhibitor of B7-CD28 interaction between T cells and antigen presenting cells, inhibited proinflammatory cytokines that can contribute to allograft rejection while sparing cytokines crucial for allograft tolerance in peripheral blood mononuclear cells from healthy cats and those with renal allografts.67 However, human or humanized antibodies may not be either effective or safe in cats. The first drug in this class licensed for use in cats is frunevetmab (Solensia, Zoetis) for osteoarthritis. Human intravenous immunoglobulin (IV-Ig) has been used extra-label in cats for treatment of some immune-mediated diseases. Derived from a pooled human donor population, IV-Ig contains human polyvalent antibodies consisting of predominantly IgG antibodies. Originally developed to treat antibody deficiency syndromes, it has become well accepted for the acute treatment of immune-mediated disease in humans. Although the mechanisms of action are poorly understood, competitive blockade of Fc receptors on macrophages, inhibition of complement activity, and alterations in T- and B-cell function may each play a role.⁶⁸ In cats, IV-Ig has been used to treat severe erythema multiforme and immune-mediated erythroid and megakaryocytic aplasia with a good outcome in two cases.^68,69 Although adverse effects were not reported in the few published case reports, it is reasonable to assume that a human-derived protein may lead to anaphylactic reactions, especially with repeated use. While IV-Ig may eventually be shown to have some utility in initial stabilization of cats with life-threatening immune-mediated disease, this expensive therapy is unlikely to have a role in chronic immunosuppression.

Small molecule kinase inhibitors include drugs such as masitinib, toceranib, and oclacitinib. Many have been developed as drugs with important roles in the treatment of cancer, but they are also used to treat immune-mediated and inflammatory diseases.70 They are labeled for treatment of various neoplastic processes and atopic dermatitis in dogs, but their mechanism of action may provide some specific instances where their use as immunomodulators may be clinically applicable in cats.

Receptor tyrosine kinases (RTKs) are enzyme-linked cell receptors that mediate downstream cellular signaling, and commercial RTK inhibitors are used in the clinic setting routinely in dogs, but so far rarely in cats. In cats, masitinib has received investigation as a novel immunotherapy therapy for asthma as it inhibits mast cell function. Cats with experimentally induced asthma treated with masitinib showed improvement in airway inflammation and pulmonary mechanics.⁷¹ Adverse effects include GI upset, dose-limiting protein losing nephropathy, and neutropenia.^71,72 The recommended dosage is 50 mg per cat PO daily or every other day; some adverse effects, such as neutropenia, may be lessened with the longer dosing interval.^71,72 Imatinib mesylate is another tyrosine kinase inhibitor that has been used off-label for the treatment of mast cell tumors and other cancers in dogs and cats. In a single case report, three cats with severe feline hypereosinophilic syndrome responded dramatically to a dose of 5 mg/day PO.⁷³

Oclacitinib is a Janus kinase inhibitor that has shown promise in feline allergic disease, including asthma and allergic dermatitis.^74,75 It appears to be well-tolerated at a dose of 0.4–0.6 mg/kg BID PO for 2 weeks, then once daily for an additional 14 days.⁷⁴

The arsenal of drugs available for therapeutic immunosuppression continues to expand at a rapid rate. However, one of the major issues for our feline patients is that these drugs are typically not specifically developed nor approved for use in cats. Caution should be adopted in the early use of new immunosuppressive drugs in cats, especially given their unique metabolic characteristics. This should not, however, prevent investigation into the use of novel immunosuppressant therapies. The hope is that each successive generation of drugs will more specifically blunt disease-inducing aspects of the dysregulated immune system while minimizing the untoward effects.

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Hepatic enzyme elevations have been documented in cats receiving itraconazole and fluconazole long-term for treatment of systemic fungal infection.1–3 Spontaneous resolution, stable elevation, resolution following dose reduction (for itraconazole, discontinuation for 2 weeks followed by initiation of half of the previous dose), and progression to fatal hepatotoxicity have all been reported.^1–4 Thus far, to the author’s knowledge, transaminase elevations have not been reported with posaconazole in cats, and resolution of an elevated ALT that developed on itraconazole was reported in a cat transitioned to posaconazole.⁵ However, clinical experience with the latter remains limited, and in humans, significant hepatotoxicity has occurred with all of the available azole antifungals.⁶ Therefore, cats receiving any azole antifungal, but particularly itraconazole, should ideally have repeat hepatic enzyme assessment within the first 2–4 weeks of therapy and periodically (e.g., monthly) thereafter. Marked or progressive elevation, or accompanying clinical signs of illness, should prompt drug discontinuation or dose reduction. Renal values should also be assessed periodically in cats receiving itraconazole, as proximal tubular changes were noted on histopathology in a safety study of the commercially available oral solution.⁴

Measurement of plasma drug concentrations has been advised in humans receiving azole antifungals (with target efficacious trough concentrations of >0.7 mcg/mL for posaconazole).⁷ A more recent publication recommended monitoring of posaconazole concentrations in cats, based on this human therapeutic trough range.⁸ However, the authors emphasized that more information about the relationship between plasma drug concentration and clinical efficacy is needed before definitive recommendations regarding target trough concentrations in cats can be made. Similar problems exist regarding therapeutic drug monitoring for other antifungals. However, because of the variable bioavailability associated with itraconazole formulations, measurement of itraconazole concentrations (peak or trough, as long as timing is consistent) may be useful in cases of treatment failure or when changing to a different formulation (see further discussion under “Pharmacokinetic Monitoring” later).

Use of chloramphenicol has been associated with myelosuppression in cats with chronic treatment; in a study of cats administered 50 mg of chloramphenicol twice daily, mean platelet count had decreased significantly by 1 week of treatment, and mean leukocyte and neutrophil counts by 3 weeks of therapy.9 Although only one cat became neutropenic during the study period, most of the cats developed lethargy, decreased appetite, and weight loss. Consequently, long-term use of chloramphenicol should be avoided when possible; if no other alternatives are feasible, empirical ­recommendations are that a CBC be monitored every 1–2 weeks during treatment, and the drug discontinued, or the dose reduced if bone marrow suppression or clinical illness occurs.

Adverse effects of sulfonamides in dogs can include idiosyncratic reactions (fever, blood dyscrasias, hepatopathy, arthropathy, dermatologic lesions, protein-losing nephropathy, meningitis, uveitis),¹⁰ keratoconjunctivitis sicca, and hypothyroidism. Anemia due to folate deficiency is a concern with prolonged high-dose treatment (90 mg/kg/day, but not 30 mg/kg/day, for 8 weeks).¹¹ Although the majority of these complications have not been documented in cats, skin reactions (presumably idiosyncratic) have been reported in two cats receiving sulfonamides,¹² and folic acid deficiency has developed in cats treated with sulfonamides and pyrimethamine (a potent folate synthesis inhibitor).¹³ As well, in one study, anemia and leukopenia developed at dosages of 300 mg/kg/day after the third week of treatment with trimethoprim–sulfadiazine, but not with 120 mg/day (approximately 30 mg/kg/day) for 1 month.¹⁴ As a result, some authors have recommended prophylactic supplementation with folinic acid in cats receiving long-term treatment with pyrimethamine and sulfonamides,¹³ and routine hematologic and biochemical monitoring in cats receiving long-term or high-dose treatment with sulfonamides or potentiated sulfonamides seems prudent, especially in patients with pre-existing anemia or leukopenia. At least monthly hematologic monitoring and recheck physical examinations should be considered and can be coordinated with clinical evaluation of drug efficacy.

Chlorambucil is a slow alkylator, and myelosuppression, gastrointestinal upset, myoclonus, and hepatic enzyme elevation have been noted in cats receiving this medication.15–18 At dosages used for feline small-cell lymphoma, myelosuppression is generally mild, but severe thrombocytopenia has been reported as late as 10 months after the start of therapy.¹⁵ Considering the variability in timing of myelosuppression, the CBC should ideally be monitored every 4–8 weeks for the duration of treatment with chlorambucil (although more frequent monitoring may be elected at the initiation of therapy). As this may be logistically difficult for owners, longer intervals can be considered if dictated by the clinical situation, but it should be understood that lack of myelosuppression in the initial phase of treatment does not indicate that it will not develop during ongoing therapy. Acquired Fanconi syndrome associated with chlorambucil has also been described in four cats (three of which were receiving a compounded preparation), and monitoring for glucosuria during treatment is recommended.¹⁹

Potential adverse effects of glucocorticoids in cats include insulin resistance (with the potential for development of overt diabetes mellitus in predisposed individuals), immunosuppression (leading to increased susceptibility to recrudescence of herpesvirus infection in the upper respiratory tract or other infections),²⁰ gastrointestinal ulceration, and increases in intravascular fluid volume with decompensation of underlying cardiac disease, as well as slow hair regrowth, muscle atrophy, behavior changes, hyperlipidemia, and the well-recognized polyuria, polydipsia, and polyphagia (although the latter tend to be less troublesome in cats than in dogs). Vacuolar hepatopathy can also develop in cats receiving glucocorticoids;²¹ however, overt hepatic or renal toxicity is not expected as consequence of treatment in otherwise stable patients. Nonetheless, it is reasonable to consider performing a CBC and chemistry panel at least every 6 months, or more frequently as dictated by the condition being treated, in cats receiving glucocorticoids, to assess for development of conditions that may compromise drug efficacy or safety. Full physical examinations semiannually are also important to detect clinical signs that might be associated with glucocorticoid excess or development of concurrent disease.

A sudden increase in water consumption, or unexplained weight loss, in a cat receiving a stable dosage of glucocorticoid should be a trigger for screening for diabetes mellitus, and fructosamine measurement may be incorporated into routine monitoring or pursued if persistent hyperglycemia is noted.

In dogs, the incidence of urinary tract infection (UTI) is higher in individuals receiving long-term glucocorticoids, and urine culture has been recommended as part of routine monitoring.²² To the author’s knowledge, a similar investigation has not been performed in cats; as well, in the canine study, many infections were subclinical, with the ultimate impact unknown. Consequently, the utility of routine urine culture during treatment of cats with glucocorticoids is unclear. Other patient factors such as presence of concurrent diseases, history of resistant or frequent UTIs, and/or the potential consequences of untreated UTIs in the individual should be considered when deciding whether to incorporate urine culture into a monitoring protocol.

As a class, nonsteroidal anti-inflammatory drugs (NSAIDs) have the potential to cause gastrointestinal irritation and ulceration, renal dysfunction or decompensation, idiosyncratic hepatotoxicity, coagulopathy, and cardiovascular complications (humans). The first two of these have been documented in cats, and three studies have examined the long-term use of two NSAIDs (meloxicam and piroxicam) for osteoarthritis and ­neoplasia, respectively, in feline patients.23–25 For both drugs, adverse events were primarily gastrointestinal (vomiting in 4% of cats receiving meloxicam, and 16% of those receiving piroxicam, typically with other ­chemotherapeutics). The meloxicam studies included cats with chronic kidney disease and did not reveal any difference between treated cats and age-matched controls with regard to development and progression of renal disease during the 6-to-12-month study period. In the study of piroxicam, no changes in hepatic or renal values were seen in the first month of therapy. A fourth study involving administration of robenacoxib for one month in cats with osteoarthritis, including cats with chronic kidney disease (CKD), found no difference in adverse events compared to placebo.²⁶ Otherwise, little data exist regarding the overall frequency of, timing of, and risk factors for adverse events related to chronic NSAID therapy in cats, and monitoring recommendations for these drugs consequently tend to incorporate information extrapolated from humans and dogs. This subject is discussed with in detail in the 2010 International Society of Feline Medicine (ISFM) and American Association of Feline Practitioners Consensus Guidelines regarding long-term NSAID treatment in cats.²⁷ A summary of suggested monitoring guidelines from this publication (which may be adapted to individual situations) is included in Box 11.1.